1. Field of the Invention
This invention relates to novel nitrosourea derivatives useful in treating various rodent tumor systems.
2. Description of the Prior Art
Cancer is now the second leading cause of death in the United States and it is believed that the proportion of deaths due to cancer will climb in coming years throughout the world due to such factors as the increase in the average life span, the large number of persons completing 20-30 years as active smokers, environmental carcinogens and the more widespread use of various preservatives in foods and other substances which are injested. The trend in cancer therapy is now in the direction of earlier and more universal use of chemotherapy alone or in conjunction with radiation and surgery, in contrast to previous use of chemotherapy as a last resort in surgically inoperative cases.
Various nitrosourea compounds have been disclosed in the literature as active therapeutic agents for the treatment of experimental and clinical neoplasms. The three members of this class which have been clinically studied are BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea], CCNU [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] and methyl CCNU [1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea]. These compounds have been shown to have activity either alone or in combination with other agents against primary brain tumors, malignant melanoma, lymphomas and a few selected solid tumors.
Johnson and his co-workers disclose BCNU, CCNU and methyl CCNU and a large number of nitrosourea analogs of these three compounds (including compounds of the formula ##STR2## where R is hydrogen or methyl) in J. Med. Chem. 14:600-614 (1971) and J. Med. Chem. 9:892-911 (1966).
Recently, attempts have been made to prepare nitrosoureas of several amino sugars including D-glucosamine, 1-amino-1-deoxy-2,3-O-isopropylidene-D-ribofuranose and 1-amino-1-deoxy-D-ribopyranose [see, for example, J. Med. Chem. 18(1):104-106 (1975) and C. R. Hebd. Seances Acad. Sci., Series D, 279(8):703-706 and 279(18):809-811(1974)]. Schein, et al., reports in Cancer Research 35:761-765 (1975) that chlorozotocin, the 2-chloroethyl analog of the anticancer antibiotic streptozotocin, has antitumor activity against the L-1210 mouse leukemia system but appears to have greatly reduced bone marrow toxicity relative to the three above-mentioned nitrosourea antitumor agents in clinical use. Chlorozotocin has the chemical name 2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose and the structure ##STR3##
Suami in Bull. Chem. Soc. Japan 46:2562-2564 (1973) suggests that the cyclopentane ring is both hydrolytically and enzymatically more stable than a ribofuranosyl moiety and discloses several cyclopentanetetrol analogs of purine nucleosides.